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US5656298A - Immunobooster for delayed release of immunogen - Google Patents

Immunobooster for delayed release of immunogen Download PDF

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Publication number
US5656298A
US5656298A US08/396,363 US39636395A US5656298A US 5656298 A US5656298 A US 5656298A US 39636395 A US39636395 A US 39636395A US 5656298 A US5656298 A US 5656298A
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immunogen
swelling agent
matrix
immunobooster
subject
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Judith P. Kitchell
Stephen C. Crooker
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DynaGen Inc
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DynaGen Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A61K9/204—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55505—Inorganic adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55555—Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers

Definitions

  • Some immunological reagents can protect persons and animals from many microbial and viral infections, from toxic incapacitation or death, and from certain noninfectious diseases. In some cases, post-onset treatment of these conditions is possible with these reagents. These immunological reagents are effective only when a proper administration regimen is followed. The proper method of administration often includes multiple sequential exposures to the immunogenic material over a period of weeks or months in order to stimulate an immunological defense. For example, in a classic immunization regimen, a single dose of vaccine, a "primer” is delivered in one injectable or oral dose, producing a short-term immunity. Vaccination is repeated one or more times, with "booster” doses, producing a secondary immune response which gives rise to a long-lasting immunity.
  • the Beck patent also describes intermittent release of antigen produced by multi-layering degradable polymer and antigen. This system requires the manufacture of a multi-layered device. The manufacturing of such a product is complex, requiring multiple production steps.
  • the immunobooster of the present invention does not require encapsulation of the immunogen to achieve the desired result of controlled release of the immunogen. Rather, the immunogen is placed in a hydrophobic polymer matrix along with a swelling agent. It is the characteristics of the polymer, the special characteristics of the swelling agent, and the relationship of the two materials in a matrix format that delays the release of the immunogen for specified periods of time after it is administered.
  • the present invention provides an immunobooster for delivering immunogen to an individual or animal.
  • the immunobooster contains an immunogen/hydrophobic polymer matrix with a swelling agent for bursting the matrix such that delivery of the immunogen occurs in a controlled release manner.
  • the swelling agent is retained by the matrix for a prolonged period of time until a certain degree of swelling has occurred, at which point the swelling bursts the immunogen polymer matrix resulting in delayed release.
  • the present invention also pertains to an immunobooster for delivering immunogen to an individual or animal that contains at least two separate immunogen formulations.
  • one of the formulations contains free immunogen which mimics the immunogen component of classical primer vaccines in which only a single dose of immunogen is included.
  • the other immunogen formulation is a combination of immunogen and swelling agent distributed in a hydrophobic polymer matrix, such that the immunogen is released upon bursting of the matrix by the swelling agent after a period of time.
  • the present invention also pertains to a method for immunizing an individual or animal by administering an immunogen/hydrophobic polymer matrix containing a swelling agent.
  • the swelling agent is capable of bursting the matrix after a period of time, thereby releasing the immunogen in a controlled release manner.
  • free immunogen will be co-administered with the immunogen/swelling agent/polymer matrix as part or, the immunobooster system.
  • the present invention also pertains to a method for preparing a hydrophobic polymer matrix containing a swelling agent and an adjuvant.
  • This matrix may contain an immunogen as well. It is permitted, however, to provide the immunogen and adjuvant in separate matrices.
  • the present invention also pertains to a method for preparing a hydrophobic polymer matrix containing a swelling agent capable of bursting the matrix.
  • this method produces the polymer matrix in the form of rods or powders.
  • the present invention also pertains to a method for preparing a polymer matrix which is capable of bursting after a prolonged period of time.
  • the method includes combining an effective amount of a swelling agent with a polymer so as to form a swelling agent/polymer matrix, and then shaping the swelling agent/polymer matrix into forms capable of being administered to an individual or animal.
  • at least one immunogen is included in the matrix.
  • the present invention further pertains to kits useful in delivering immunogen to an individual or animal in a controlled release manner.
  • the kit includes a packaged immunogen/polymer matrix with a swelling agent for bursting the matrix.
  • the kit also contains a liquid suspending vehicle for the matrix and instructions providing information to the user regarding the use of the immunogen/swelling agent/polymer matrix for delivering immunogen in a controlled release manner.
  • the kit also contains a package of free immunogen.
  • Still another object of the invention is to administer an immunogen to an individual or animal in a pulsed release manner, such that there is a prolonged period of time between the time of the initial administration of an immunogen-containing formulation and release of the immunogen into the individual or animal.
  • FIG. 1 depicts a kit including a package containing an immunogen/polymer matrix with a swelling agent, free immunogen, suspending vehicle, syringe and instructions.
  • FIG. 2 depicts in vitro swelling of 10% dried aluminum hydroxide gel/PLGA rods of differing polymer substituent ratios as a function of time.
  • FIG. 3 depicts in vitro swelling of 0-20% dried aluminum hydroxide gel rods as a function of time.
  • FIG. 4 depicts swelling of 8.5% dried aluminum hydroxide gel rods, prepared either with dried aluminum hydroxide gel as purchased or with swollen and redried aluminum hydroxide gel, as a function of time.
  • FIG. 5 depicts in vitro swelling and release of immunogen (Hepatitis A Vaccine), as measured by the percent of HAV binding in an ELISA assay from dried aluminum hydroxide gel/PLGA/Hepatitis A Vaccine rods as a function of time.
  • FIG. 6 depicts in vitro swelling and release of aluminum hydroxide gel-bound immunogen (Hepatitis A Vaccine) as measured by the percent of HAV binding in a HAV ELISA assay, from dried aluminum hydroxide gel/PLGA/aluminum hydroxide-Hepatitis A Vaccine rods as a function of time.
  • Al hydroxide gel-bound immunogen Hepatitis A Vaccine
  • FIG. 7 depicts the in vivo activity of immunobooster when given along with a primer dose of aluminum hydroxide gel-Hepatitis A Vaccine as measured by the serum level of anti-HAY antibody (seroconversion) in mice. Also shown is the lack of activity when the immunobooster is given without primer.
  • the present invention pertains to an immunobooster for delivering an immunogen to a subject.
  • the immunobooster includes an immunogen/hydrophobic polymer matrix containing a swelling agent which is capable of causing a delayed bursting of the matrix.
  • the immunobooster is constructed and arranged to deliver the immunogen to the subject in a controlled release manner.
  • the term immunobooster means at least one immunogen formulation which can produce a secondary immune response.
  • the immunobooster may also include an immunogen formulation which produces a primary immune response.
  • a primary immune response produces a short-term immunity, and results from initial exposure to an immunogen.
  • a secondary immune response produces a long-lasting immunity, and results from multiple exposure to the same immunogen.
  • a different immunogen formulation for producing the primary response can be administered physically independently of, or in conjunction with, the immunobooster of the invention. Preferably if two separate formulations are co-administered, then they are administered at about the same time.
  • the immunobooster includes both an immunogen formulation from which immunogen is released at the time of administration, producing the primary immune response, and a second immunogen formulation which releases immunogen after a period of time subsequent to administration of the immunobooster, thus producing the secondary immune response.
  • This second immunogen formulation is an immunogen/swelling agent/polymer matrix which is designed to burst after a period of time, releasing the immunogen.
  • the immunobooster may contain one or it may contain multiple controlled release immunogen formulations which release immunogens at different times subsequent to administration of the immunobooster.
  • the delayed release of immunogen from the immunobooster is a function of the type and amount of a swelling agent in the immunogen/polymer matrix and of the exact polymer utilized.
  • the matrix at first is able to retain the swelling agent and immunogen, but after a delay, the swelling agent bursts the matrix, releasing the immunogen into the subject.
  • the term controlled release of immunogen is intended to include release of immunogen from the immunobooster such that total release does not occur immediately upon administration of the immunobooster.
  • pulsed release of immunogen is intended to include release of immunogen after administration of the immunobooster such that release occurs in a discrete burst after a prolonged period of time subsequent to the administration. In some circumstances, there might be a low level of release upon administration which continues for some period of time until a burst releasing a high level of immunogen occurs.
  • the term prolonged period of time is intended to encompass a period of time sufficient to permit the desired secondary immunologic response to the release of the immunogen from the immunogen/polymer matrix. This period varies depending upon at least such factors as the particular immunogen used, the amount of immunogen used in the immunobooster, the amount of immunogen used originally to elicit the primary immune response, and the type of species being immunized. Typical time periods would be 3 weeks, 6 weeks, 3 months, 6 months, and 12 months.
  • certain currently accepted immunization regimens include the following.
  • the recommended administration times are a first dose at elected date; a second dose at 1 month after first dose; and a third dose at 5 months after second dose. See Product Information, Physician's Desk Reference, Merck Sharp & Dohme (1990), at 1442-43.
  • the recommended administration for children is first dose at elected date (at age 6 weeks old or older); a second dose at 4-8 weeks after first dose; a third dose at 4-8 weeks after second dose; a fourth dose at 6-12 months after third dose; a fifth dose at age 4-6 years old; and additional boosters every 10 years after last dose.
  • Desired time intervals for delivery of multiple doses of a particular immunogen can be determined by one of ordinary skill in the art employing no more than routine experimentation.
  • an appropriate amount of swelling agent, an appropriate degree of hydration of the swelling agent, and an appropriate polymer are chosen for the immunobooster, such as to cause the immunogen/polymer matrix to burst at the desired time interval.
  • immunogen is intended to include any substance which is capable, under appropriate conditions, of inducing the formation of antibodies and/or inducing cellular immunity.
  • the formation of antibodies depends on at least such factors as introduction of the immunogen into an appropriate species, on the quantity of immunogen introduced, and on the route and frequency of introduction.
  • Immunogens include proteins, polysaccharides, nucleoproteins, lipoproteins, polypeptides, and small molecules suitably linked to proteins, polypeptides or other carrier molecules. Examples of immunogens are inactivated hepatitis A virus, polio virus, inactivated feline leukemia virus, and malarial vectors, e.g., sporocite surface peptides.
  • the term free immunogen is intended to mean immunogen that is in a form that is available substantially upon administration for inducing a primary immune response. Such forms have been in use for many years and are well known to those of ordinary skill in the art. It includes immunogen that is not incorporated in a matrix such as a polymer matrix. The free immunogen may or may not be bound to an adjuvant (a material which enhances the cellular response to immunogens). The free immunogen is delivered to the subject, acting as the equivalent of a "primer" dose in a classic multiple administration immunization regimen. In such a configuration, the immunobooster would also contain at least a second immunogen formulation as part of the immunogen/polymer matrix for delivery of a "booster" dose after a period of time.
  • the immunogen/swelling agent/polymer matrix may include immunogen adsorbed to a colloidal adjuvant such as aluminum hydroxide gel or immunogen covalently bonded to an adjuvant.
  • the adjuvant also may be a separate component in the matrix along with the immunogen. Still further, adjuvant may be present in a separate polymer/swelling agent matrix.
  • the immunogen may be combined prior to incorporation in the polymer matrix, forming an immunogen-adjuvant complex.
  • the immunogen-adjuvant complex may be distributed in a homogeneous fashion throughout the matrix.
  • complexed immunogen is intended to include immunogen that is covalently linked or adsorbed onto the adjuvant.
  • polymer is intended to include molecules composed of monomers which do not have significant adverse physiological effects when administered in vivo.
  • a polymer made from more than one kind of monomer is called a copolymer.
  • Polymers may be natural or synthetic.
  • the polymers useful in the invention are hydrophobic. By hydrophobic it is meant that the formed polymer matrix, absent a swelling agent, would not attract water and swell very much in an aqueous environment.
  • the polymer is biodegradable.
  • a biodegradable polymer means polymers capable of degrading in vivo.
  • biodegradable polymers which may be used in this invention include poly (lactic/glycolic) acid copolymers (PLGA), polylactic acid (PLA), polyglycolic acid (PGA), polyesters, e.g., polyorthoesters, polylactones, polyanhydrides and polyaminoacids.
  • Polymers prepared from glycolida and lactide dimers, e.g., PLGA, PLA and PGA are known to undergo slow hydrolysis when implanted in tissue; the by-products of their hydrolysis (lactic and glycolic acids) are normal metabolites.
  • polymers are generally believed to be non-toxic, are relatively non-inflammatory, and are non-tissue reactive. These polymers also exhibit moderate tensile and compressive strength and pliability.
  • Poly (L lactic) acid is the optically active form of the lactic acid polymer.
  • Poly DL lactic acid is an optically inactive form of the polymer.
  • the preferred biodegradable polymer is PLGA.
  • PLGA copolymers can be composed in either poly (DL-lactic/glycolic) acid or poly(L-lactic/glycolic) acid forms.
  • the specific lactide/glycolide ratio of the PLGA polymer and the molecular weight (size) distribution of the polymer are factors considered when designing the immunobooster.
  • the choice of which PLGA to use is determined by the desired release duration for the immunogen.
  • the preferred polymers are in the range of about 95:5 D,L lactide/glycolide to about 40:60 D,L lactide/glycolide, most preferably about 50:50.
  • the preferred polymers have weight average molecular weights (M w ) in the range of about 40,000 to about 300,000 daltons, most preferably about 50,000 daltons.
  • the preferred polydispersity (M w /M n ) is about 2.
  • the term matrix is intended to include a composite of polymer and one or more other components which are distributed in a homogeneous fashion throughout the matrix.
  • the polymer and components are compressed so that the polymer closely conforms to the components if the components are particulate, or so that one or more components are dissolved in the polymer.
  • the components may include immunogen-adjuvant complex, immunogen, swelling agent and adjuvant.
  • the matrix is made of a material capable of being shaped into various forms, e.g., a nanoparticle, a microparticle or a monolithic rod, sphere or other shape.
  • the preferred form for the matrix is a rod or powder. A method for the preparation of such rods and powder is described in Example 1.
  • immunogen/polymer matrix is intended to include a matrix of polymer and immunogen. Such a matrix may also include other components, e.g., a swelling agent.
  • the immunogen is complexed with an adjuvant prior to incorporation in the polymer matrix.
  • the immunogen is not complexed to adjuvant in the immunogen/polymer matrix.
  • the matrix may also contain adjuvant or the immunobooster may contain a separate formulation which releases adjuvant at the same time as the immunogen is released.
  • non-aqueous immunogen/polymer matrix is intended to include any immunogen/polymer matrix that is substantially free of water. Preferably it contains no water. Some water may be present as long as the amount of water does not impede or detrimentally affect the desired timing of release of immunogen from the matrix.
  • the term swelling agent is intended to include any substance which exhibits biphasic swelling characteristics in an aqueous environment (i.e. a slow swelling phase followed by a rapid swelling phase), such that if it is part of an immunogen/polymer matrix, it can, upon reaching a rapid swelling phase, burst the matrix after a prolonged period of time subsequent to administration of the matrix into a subject. Typical time periods of delay would be 2 weeks to 6 months.
  • the preferred swelling agent when dispersed in an immunogen/polymer matrix, initially effects changes in the volume of the matrix very slowly, resulting in retention of the immunogen in the matrix. After a period of time, the swelling agent swells the matrix rapidly, allowing the bulk of the immunogen to be released in a pulsed manner.
  • the swelling agent should be sufficiently dry and should be present in sufficient amount in the matrix so that when the matrix is introduced into an aqueous environment, it will swell sufficiently to burst the matrix used in the immunobooster.
  • the preferred swelling agent is also an adjuvant
  • non-aqueous swelling agent formulation is intended to include a swelling agent formulation containing preferably no water. Some water may be present as long as the amount of water does not detrimentally affect the swelling agent's intended function of bursting the matrix.
  • the preferred swelling agents of this invention swell very slowly in water.
  • the preferred range for equilibration for a mixture of water and dried aluminum hydroxide gel to form a 1% gel is one week to four weeks.
  • swelling agents are: aluminum hydroxide; aluminum phosphate; calcium phosphate; lanthanum, cerium, and cadmium salts; and bentonite (colloidal hydrated aluminum silicate).
  • the preferred swelling agent is dried aluminum hydroxide gel.
  • the dried gel is also known as aluminum hydroxide hydrate (Al 2 O 3 •XH 2 O or AL(OH) 3 •XH 2 O).
  • Liquid slurry forms of aluminum hydroxide gel are well-known adjuvants and are often referred to as Alum or Alum gel by immunologists.
  • Alhydrogel is a trade name for liquid aluminum hydroxide gel.
  • An effective amount of the swelling agent is used in the immunogen/polymer matrix.
  • An effective amount of swelling agent is that amount capable of bursting in an aqueous environment the immunogen/polymer matrix after a prolonged period of time so as to release the immunogen.
  • increasing the amount of swelling agent delays the onset of rapid swelling.
  • An effective amount can be determined by considering at least the swelling agent used, the polymer used, the particular size and geometry of the shaped polymer matrix, and the time period desired to elapse before the swelling agent bursts the polymer matrix. An effective amount can be determined by one of ordinary skill in the art employing such factors using no more than routine experimentation.
  • a PLGA polymer matrix designed to release immunogen from the matrix in about two to six weeks subsequent to administration into a subject might contain 10% dried aluminum hydroxide gel incorporated into 50:50 D,L lactide/glycolide.
  • Example 1 describes the preparation of dried aluminum hydroxide gel/PLGA rods and powder.
  • Means for preparing the immunobooster include the mixing of dry immunogen plus dry adjuvant, or addition of dry adjuvant-immunogen complex, swelling agent and polymer. If the adjuvant, the adjuvant-immunogen complex, or the swelling agent are suspensions or solutions in buffer, it is preferable to remove the buffer prior to incorporation in the polymer.
  • this gel is also released with immunogen absorbed on similar gel, or co-resident non-complexed immunogen from the immunogen/polymer matrix upon bursting of the matrix.
  • the released aluminum hydroxide gel also acts as an adjuvant.
  • other adjuvants may be incorporated into the immunogen/polymer matrix, either complexed with immunogen or as a separate component, which upon bursting of the matrix are released along with immunogen, or a separate formulation may be delivered.
  • adjuvant is intended to include any substance which is incorporated into or administered simultaneously with the immunogen which potentiates the immune response in the subject.
  • Adjuvants include aluminum compounds, e.g., gels, aluminum hydroxide and aluminum phosphate gels, and Freund's complete or incomplete adjuvant (in which the immunogen is incorporated in the aqueous phase of a stabilized water in paraffin oil emulsion).
  • the paraffin oil may be replaced with different types of oils, e.g., squalene or peanut oil.
  • BCG attenuated Mycobacterium tuberculosis
  • calcium phosphate calcium phosphate
  • levamisole isoprinosine
  • polyanions e.g., poly A:U
  • leutinan pertussis toxin
  • lipid A saponins
  • peptides e.g., muramyl dipeptide.
  • Rare earth salts e.g., of lanthanum and cerium, may also be used as adjuvants.
  • the preferred adjuvant is dried aluminum hydroxide gel. The amount of adjuvant required depends upon the subject and the particular adjuvant and immunogen used in the immunobooster and can be readily determined by one skilled in the art without undue experimentation.
  • Administration of the immunobooster of this invention may be made by any method which allows the immunogen to be delivered to the subject.
  • Typical methods of administration use an immunobooster which can deliver immunogen orally, by injection or by implantation.
  • the preferred method is by injection into the tissues of the subject. Injections include intradermal, subcutaneous, intramuscular and intraperitoneal administration.
  • the immunobooster may be administered as a liquid suspension or as a solid dose.
  • subject is intended to include mammals.
  • the subject is an animal that is commercially used as livestock, a pet, or a human being.
  • effective immunization is intended to include that degree of immunization which protects the individual or animal from an infectious or noninfectious disease, toxic incapacitation or death, or which mitigates the effects of such diseases or exposures. Effective immunization often requires multiple sequential exposure to the immunogen over a period of weeks or months. An effective amount of an immunobooster is that amount which is sufficient to invoke the secondary immune response.
  • This invention also pertains to a method for immunizing an individual or animal in such a way so that the need for multiple administrations of a particular immunogen is alleviated. Such immunization is accomplished by administering to the individual or animal the immunobooster described above.
  • This invention further pertains to a method for preparing a polymer matrix including a swelling agent.
  • the method involves combining an effective amount of a swelling agent with a polymer forming a swelling agent/polymer matrix.
  • the method also involves the step of shaping the swelling agent/polymer matrix into forms capable of being administered to a subject.
  • the swelling agent/polymer matrix also includes an immunogen.
  • the immunogen preferably is incorporated into the matrix, prior to shaping.
  • the matrix may be prepared by dissolving the polymer in a solvent.
  • the solvent is selected based on its ability to dissolve the polymer.
  • One of ordinary skill in the art would know what solvent to select for a particular polymer based on such factors as polymer solubility, ease of removal, compatibility with the immunogen and toxicity.
  • An example of a solvent useful for dissolving PLGA is methylene chloride.
  • the swelling agent as defined above, is added to the solution.
  • the suspension of the immunogen, polymer, solvent, adjuvant and swelling agent may be cast on a plate. The casting is dried and extruded or molded into the desired form, e.g., beads or rods which can be further processed into powder by grinding.
  • an immunogen is added to the suspension prior to casting.
  • the method produces rods or powder of a polymer matrix which contain a swelling agent.
  • the preferred polymer is PLGA and the preferred swelling agent is dried aluminum hydroxide gel.
  • the dried aluminum hydroxide gel comprises between about 1% and about 40% of the matrix. More preferably it comprises between about 5% and about 20% of the matrix. Most preferably it comprises between about 10% and about 15% of the matrix.
  • kits useful in delivering immunogen to an individual or animal contain an immunobooster according to the invention, as well as instructions for use.
  • the kit 8 as shown in FIG. 1 may contain at least one packaged immunogen/polymer matrix 10 including a swelling agent with instructions 14 providing information to the user regarding the use of the matrix.
  • a suspending vehicle 12 may be included.
  • the number of packages may correspond to that number, with each package containing a different immunogen/polymer matrix with swelling agent, designed to burst after different periods of time subsequent to administration of the immunobooster.
  • a package containing free immunogen 16 is also provided in the kit.
  • a syringe 18 may also be provided. The syringe 18 may be preloaded with a particular immunogen/polymer matrix including swelling agent. If free immunogen is provided in the kit, the syringe 18 may also be preloaded with the free immunogen.
  • the weight of the recovered material was 2.9718 g.
  • 30 ml methylene chloride was added to the dry polymer.
  • the suspension was stirred, then cast under nitrogen on a glass plate and spread with a Boston Bradley blade (gap set at 0.025 inch thickness).
  • the casting was vacuum dried and 2.5385 g was recovered (77% yield). The casting was extruded at 55°-65° C. Pliable rods were obtained.
  • Two polymer/dried aluminum hydroxide gel matrices were prepared as described in Example 1.
  • the polymers used were: 50:50 DL PLGA; and 85:15 DL-lactide/glycolide.
  • Polymer/dried aluminum hydroxide gel castings (10% gel) were prepared as described in Example 1, except that they were not cast under nitrogen. The castings were extruded into rods. The rods were cut into 1 cm lengths and accurately measured. The initial volume of each rod was calculated. The rods were placed in separate vials with phosphate buffered saline and maintained at 37° C. Periodically the rods were remeasured and new volumes were calculated.
  • the rods made with the 50:50 DL PLGA showed biphasic swelling behavior in the period measured (49 days). After remaining at a swelling of about 20% for 4 weeks, the rods swelled rapidly and during weeks 5-7 showed surface bumps, breakage, and release of particles.
  • the rods made with the 85:15 PLGA remained at relatively constant volume (about 20% increase from initial volume) for seven weeks and no bubbles or ruptures appeared. The results are shown in FIG. 2.
  • volume changes of PLGA rods differing in dried aluminum hydroxide gel content were measured as a function of time by the procedure described in Example 2. The results are shown in FIG. 3.
  • PLGA rods containing no aluminum hydroxide gel swelled slightly.
  • Increasing amounts of dried aluminum hydroxide gel over the range of 5-8.5% caused increased delays in swelling and very large increases in volume.
  • Matrix containing 20% dried aluminum hydroxide gel swelled much more rapidly, indicating that the limit of loading preferably is between 8.5% and 20% for that matrix system.
  • Rods of 8.5% dried aluminum hydroxide gel/PLGA were prepared either with dried aluminum hydroxide gel as purchased or with swollen and redried aluminum hydroxide gel.
  • the rods were prepared as described in Example 1 with the following modifications. After filtration the PLGA/methylene chloride solution was not dried and reweighed. The addition of components and casting steps were done in a fume hood rather than under nitrogen. The swollen and redried aluminum hydroxide gel was prepared as follows.
  • a 1 mg/ml dried aluminum hydroxide gel suspension in phosphate buffered saline was prepared by stirring for 5 days at 37° C. in six Oak Ridge type centrifuge tubes. The tubes were centrifuged 25 minutes at 12,5000 rpm. The supernatants were removed and the pellets were then washed three times with freshly drawn Milli Q® water (Resistivity>18 M ⁇ •cm). After centrifugation, the pellets were vacuum dried for 6 days in a dessicator at room temperature and 0:1249 grams reswollen and dried gel was recovered.
  • HAV Hepatitis A Vaccine
  • the extracted HAV sample was approximated to have a volume of 520 ⁇ l. It was added to a micro-concentrator unit with a 30,000 MW cutoff (Amicon #4208). The concentrator unit had been pre-rinsed by passing freshly drawn Milli-Q R water (Resistivity>18 M ⁇ •cm) through the unit. The assembled unit was centrifuged for a total of 90 minutes at 5,000 rpm in an SS•34 rotor in an RC-5B centrifuge. The concentrated HAV material was collected in a retentate cup provided with the unit and a steady, but very gentle stream of nitrogen was blown onto the liquid to dry the material. After ⁇ 30 minutes, a small amount of film-like material remained in the retentate cup. All of this material was used as described below.
  • a PLGA stock solution was prepared by addition of 100 ml HPLC grade CH 2 Cl 2 to 10 grams 50:50 DL PLGA. The mixture was stirred overnight to dissolve the polymer. A considerable amount of fine gel-like particles remained undissolved. The liquid was filtered to remove this undissolved material. The liquid was pressure filtered through a prefilter backed by a 5 ⁇ m Teflon filter (Millipore Type LS). The weight of PLGA per volume of solution after filtration was determined to be 0.1005 g PLGA/ml filtrate.
  • the liquid was stirred rapidly to suspend the fine dried aluminum hydroxide gel particles and to try to break up the larger dried HAV film particles.
  • the suspension was cast on a glass plate with a Boston-Bradley Blade (gap ⁇ 0.025 inches) and allowed to air dry for ⁇ 21/2 hours when the homogeneous film was removed with a razor blade scraper and placed under vacuum to finish drying.
  • the vacuum dried casting (0.9517 g) was extruded into rods.
  • the extrusion conditions were 62°-67° C. and ⁇ 5,000 lbs applied load.
  • the resulting 0.43 grams of rod were flexible and opaque gray in color.
  • a batch of aluminum hydroxide gel adsorbed-HAV was prepared from inactivated and partially purified antigen.
  • the aluminum hydroxide gel adsorbed-HAV was lyophilized.
  • An aliquot of 83 ⁇ l of Alhydrogel solution was added to 2.5 ml of a solution containing 55 ⁇ g of HAV in a lyophilization flask fitted with magnetic stir bar.
  • a variation of the lyophilization procedure described in European Patent #0130619 (date Mar. 15, 1989, application number 84107773.8) was carried out with aluminum hydroxide gel-HAV. After mixing for 30 minutes, a 500 ⁇ l aliquot was removed.
  • a solution of 50:50 DL PLGA was prepared by stirring 10 g PLGA in CH 2 Cl 2 .
  • the solution was passed through a series of stainless steel screens to remove gel particles, finally passing a 38 ⁇ m screen.
  • This filtrate was pressure filtered, ⁇ 25 ml at a time, through a 1 ⁇ m retention glass, binder-free prefilter backed up by a 5 ⁇ m Teflon R filter.
  • the filtrate was collected in a 500 ml Teflon R bottle. After removal of an aliquot for residual PLGA determination, the volume of filtrate was 120 ml and the concentration was 0.064 g PLGA/ml.
  • the dried aluminum hydroxide gel was stirred to remove the lyophilized material from the flask walls.
  • the combined materials were added to the PLGA filtrate.
  • the suspension was cast onto 3 glass plates with a casting blade set at 0.025 inches. The glass plates were placed on racks in a drying chamber that had a steady stream of nitrogen passing through. After ⁇ 2 hours, the cast films were scraped from the glass plates and vacuum dried. The casting was extruded into rods. The rods were ground to a powder and the powder was sieved to obtain the fraction of 38-90 ⁇ m. 1.87 g was obtained.
  • Example 6 two types of in vitro studies (measurements of HAV release over time and rod swelling) were carried out with the formulation described in Example 7. Release studies were done on extruded rods cut into segments of ⁇ 25 mm. Three segments were weighed ( ⁇ 100 mg total) and transferred to each of three microcentrifuge tubes. An aluminum hydroxide gel containing buffer was prepared with Alhydrogel (1:20 dilution in PBS with 0.1% NaN 3 ) and was added to each of the samples. All samples were maintained at 37° C. At intervals, the samples are transferred to fresh Alhydrogel. The leachates were centrifuged and the pellets were assayed for HAV content by ELISA. This formulation showed HAV release beginning at Day 23. The initiation of rapid swelling was noted on Day 25. The volume changes and aluminum hydroxide gel adsorbed-HAV release profile for this formulation are shown in FIG. 6.
  • the in vivo test was designed to test both the ability of the immunobooster formulation to give a booster-like effect when given along with a primer dose of aluminum hydroxide gel-HAV and its ability to give a delayed release of the gel-bound HAV.
  • the amount of primer dose given (0.15 ml) was that previously determined to give a positive result in a anti-HAV antibody ELISA test [seroconversion] in about half of a group of inoculated mice.
  • the control groups in the study were: (1) vehicle control (aluminum hydroxide gel); (2) primer only; and (3) primer plus booster (a second dose of primer given at 4 weeks).
  • the immunobooster dose (1 ⁇ ) contained approximately the same amount of HAV as that given in primer and booster doses (10-35 ng HAV/dose).
  • the study groups were as follows: two groups received one primer dose injected simultaneously with the immunobooster at 1 ⁇ or 5 ⁇ , suspended in a carboxymethylcellulose solution, and one group received immunobooster alone, suspended in carboxymethylcellulose solution, at 5 ⁇ .
  • the test animals were CD-1 VAF male mice (28-34 g) from Charles River Laboratories. The Groups are summarized in Table 1.
  • the animals were bled from the orbital sinus at 4, 6, 8 and 10 weeks.
  • the sera were analyzed neat and at various dilutions by an antibody HAV ELISA test which returns number of positive test results [seroconversions] per number of animals in the set at each dilution tested.
  • the results are summarized by calculating the dilution at which each set of animals showed 50% seroconversion at each time point. The results are shown in graphical form in FIG. 7. It can be seen that while the immunoboosters alone have never given a significant amount of seroconversion, animals receiving the immunobooster along with a primer dose showed levels of anti-HAV equal to or higher than the levels seen in animals receiving primer plus traditional 4 week booster shots, and significantly higher than those receiving primer alone.

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US20040001872A1 (en) * 2002-06-11 2004-01-01 Chung Shih Biodegradable block copolymeric compositions for drug delivery
US20040185101A1 (en) * 2001-03-27 2004-09-23 Macromed, Incorporated. Biodegradable triblock copolymers as solubilizing agents for drugs and method of use thereof
US20050202072A1 (en) * 1999-04-16 2005-09-15 Novo Nordisk A/S Dry mouldable drug formulation
US20070161048A1 (en) * 2004-02-16 2007-07-12 Tsukao Yokoyama Anti nc1 monoclonal antibody
WO2011088229A3 (fr) * 2010-01-13 2012-01-05 The Regents Of The University Of Michigan Système de biomatériau auto-réparateur actif
US8454997B2 (en) 2001-12-18 2013-06-04 Novo Nordisk A/S Solid dose micro implant
US8629151B2 (en) 2009-05-27 2014-01-14 Selecta Biosciences, Inc. Immunomodulatory agent-polymeric compounds
US9066978B2 (en) 2010-05-26 2015-06-30 Selecta Biosciences, Inc. Dose selection of adjuvanted synthetic nanocarriers
US10682442B2 (en) 2014-04-04 2020-06-16 University Of Kentucky Research Foundation Small molecule drug release from in situ forming degradable scaffolds incorporating hydrogels and bioceramic microparticles
US10933129B2 (en) 2011-07-29 2021-03-02 Selecta Biosciences, Inc. Methods for administering synthetic nanocarriers that generate humoral and cytotoxic T lymphocyte responses
WO2022152939A1 (fr) 2021-01-18 2022-07-21 Conserv Bioscience Limited Compositions immunogènes de coronavirus, méthodes et utilisations de celles-ci

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JP2000507912A (ja) * 1995-08-31 2000-06-27 アルカームズ コントロールド セラピューティックス，インコーポレイテッド 作用剤の徐放性組成物
EP1579851A3 (fr) * 1997-08-29 2009-09-02 Corixa Corporation Agents bioactifs encapsulés à libération rapide servant à initier ou à potentialiser une réponse immunitaire, et procédés d'utilisation de ceux-ci
AU760034B2 (en) * 1997-08-29 2003-05-08 Corixa Corporation Rapid release encapsulated bioactive agents for inducing or potentiating an immune response and methods of using thereof
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US20050202072A1 (en) * 1999-04-16 2005-09-15 Novo Nordisk A/S Dry mouldable drug formulation
US8084053B2 (en) 1999-04-16 2011-12-27 Novo Nordisk A/S Dry mouldable drug formulation
US20100196477A1 (en) * 1999-04-16 2010-08-05 Novo Nordisk A/S Dry Mouldable drug formulation
US20030234466A1 (en) * 2000-07-14 2003-12-25 Rasmussen Thomas Buch Method of moulding a pharmaceutical composition in a packaging material
US20040185101A1 (en) * 2001-03-27 2004-09-23 Macromed, Incorporated. Biodegradable triblock copolymers as solubilizing agents for drugs and method of use thereof
US8454997B2 (en) 2001-12-18 2013-06-04 Novo Nordisk A/S Solid dose micro implant
US8642666B2 (en) 2002-06-11 2014-02-04 Protherics Salt Lake City, Inc. Biodegradable block copolymeric compositions for drug delivery
US7649023B2 (en) 2002-06-11 2010-01-19 Novartis Ag Biodegradable block copolymeric compositions for drug delivery
US20090264537A1 (en) * 2002-06-11 2009-10-22 Protherics Salt Lake City, Inc. Biodegradable block copolymeric compositions for drug delivery
US20100076067A1 (en) * 2002-06-11 2010-03-25 Chung Shih Biodegradable block copolymeric compositions for drug delivery
US9265836B2 (en) 2002-06-11 2016-02-23 Protherics Salt Lake City, Inc. Biodegradable block copolymeric compositions for drug delivery
US20040001872A1 (en) * 2002-06-11 2004-01-01 Chung Shih Biodegradable block copolymeric compositions for drug delivery
US8039226B2 (en) * 2004-02-16 2011-10-18 Tsukao Yokoyama Anti NC1 monoclonal antibody
US20070161048A1 (en) * 2004-02-16 2007-07-12 Tsukao Yokoyama Anti nc1 monoclonal antibody
US9884112B2 (en) 2009-05-27 2018-02-06 Selecta Biosciences, Inc. Immunomodulatory agent-polymeric compounds
US8629151B2 (en) 2009-05-27 2014-01-14 Selecta Biosciences, Inc. Immunomodulatory agent-polymeric compounds
US9006254B2 (en) 2009-05-27 2015-04-14 Selecta Biosciences, Inc. Immunomodulatory agent-polymeric compounds
US20150125531A1 (en) * 2010-01-13 2015-05-07 The Regents Of The University Of Michigan Active self-healing biomaterial system
US20120288537A1 (en) * 2010-01-13 2012-11-15 The Regents Of The University Of Michigan Active self-healing biomaterial system
WO2011088229A3 (fr) * 2010-01-13 2012-01-05 The Regents Of The University Of Michigan Système de biomatériau auto-réparateur actif
US10220001B2 (en) * 2010-01-13 2019-03-05 The Regents Of The University Of Michigan Active self-healing biomaterial system
US9066978B2 (en) 2010-05-26 2015-06-30 Selecta Biosciences, Inc. Dose selection of adjuvanted synthetic nanocarriers
US9764031B2 (en) 2010-05-26 2017-09-19 Selecta Biosciences, Inc. Dose selection of adjuvanted synthetic nanocarriers
US10933129B2 (en) 2011-07-29 2021-03-02 Selecta Biosciences, Inc. Methods for administering synthetic nanocarriers that generate humoral and cytotoxic T lymphocyte responses
US10682442B2 (en) 2014-04-04 2020-06-16 University Of Kentucky Research Foundation Small molecule drug release from in situ forming degradable scaffolds incorporating hydrogels and bioceramic microparticles
WO2022152939A1 (fr) 2021-01-18 2022-07-21 Conserv Bioscience Limited Compositions immunogènes de coronavirus, méthodes et utilisations de celles-ci

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